✍🏼 Yuqi Wang, Quan Quan, Camille Gleason, Helin Yu, Lujia Peng, Yanshen Kang, Ling Jiang,Kailun Wu, Jie Pan,Moxiyele Bao, Qing Zhu, Meiqi Yi, Ming Fang, Yue Zheng, Ling Qiu, Bin Xu, Xiang Li, Jinfeng Song, Jiamu Sun, Zheng Zhang, Zijun Su, Jara Lin, Yuanyuan Xie, April Xu, Xiling Song, Chichi Huang, Zhirong Shen, Lai Wang, Jing Song

🏠 Department of Research and Development, BeiGene (Beijing) Co. Ltd, Beijing, China

📑 mAbs (2023)

Abstract
Pharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool can be used to produce materials for the toxicology (Tox) study, reducing time to the clinic by 4–5 months. During the coronavirus disease 2019 (COVID-19) pandemic, the anti-COVID drugs timeline from DNA transfection to the clinical stage was decreased to 6 months using a stable pool to generate a clinical drug substrate (DS) with limited stability, virus clearance, and Tox study package. However, a lean chemistry, manufacturing, and controls (CMC) package raises safety and comparability risks and may leave extra work in the late-stage development and commercialization phase. In addition, whether these accelerated COVID-19 drug development strategies can be applied to non-COVID projects and established as a standard practice in biologics development is uncertain. Here, we present a case study of a novel anti-tumor drug in which application of “fast-to-FIH” approaches in combination with BeiGene’s de-risk strategy achieved successful delivery of a complete CMC package within 10 months. A comprehensive comparability study demonstrated that the DS generated from a stable pool and a single-cell-derived master cell bank were highly comparable with regards to process performance, product quality, and potency. This accomplishment can be a blueprint for non-COVID drug programs that approach the pace of drug development during the pandemic, with no adverse impact on the safety, quality, and late-stage development of biologics.

How the WOLF was used in this study
The researchers incorporated use the WOLF cell sorter as part of their cell line generation workflow. Specifically, after establishing a stable cell pool expressing the therapeutic antibody of interest, they used the WOLF to perform single-cell cloning by isolating individual cells into wells for expansion and characterization. This microfluidic sorter enabled selection of single cells from the heterogeneous pool—with or without fluorescent markers—based on flow cytometric parameters and gentle, low-pressure sorting, which improved the efficiency of isolating truly monoclonal cell clones compared to traditional limiting dilution methods. The sorted single-cell clones were then expanded and evaluated for productivity, quality attributes, and other phenotypes critical for advancing candidate biologic drugs toward first-in-human trials.